Precise control of arterial diameter throughout the body is essential to maintain perfusion pressure and blood flow to vital organs, such as the brain. Ca2+ influx through L-type voltage-dependent Ca2+ channels (VDCCs) has traditionally been viewed as the major Ca2+ entry pathway in arterial smooth muscle (ASM) that controls contraction and the regulation of arterial diameter. Here, we provide direct evidence for a second major Ca2+ entry pathway in some types of ASM?the transient receptor potential vanilloid 1 (TRPV1) channel, a ?non-selective? Ca2+-permeable ion channel typically involved in nociception in sensory nerves. Using ?optical patch-clamping? techniques, we provide the first measurements of Ca2+ influx through single TRPV1 channels (?sparklets?). Importantly, our preliminary data also demonstrate engagement of ASM TRPV1 channels by activation of ?1-adrenergic receptors (?1-ARs)?the major vasoconstrictor pathway of the sympathetic nervous system (SNS). The role of the SNS in maintaining cerebral blood flow (CBF) is particularly important during episodes of acute hypotension (e.g., hemorrhagic shock) and is achieved in part through ?1- AR?mediated vasoconstriction in peripheral tissue. Our overarching hypothesis is that, in response to acute decreases in blood pressure, constriction of non-brain arteries possessing ASM TRPV1 channels tunes vascular resistance to redistribute blood to cerebral arteries, which we have found to lack TRPV1 channels. Within Aim 1, we explore the basis of TRPV1 activation by ?-ARs. The goal of this aim is to unravel the linkages between ?1-ARs, ASM TRPV1 channels, Ca2+ signaling and arterial diameter. We believe the differential expression of TRPV1 and the activation of this channel by ?1-AR ligands play important roles in the regulation ASM Ca2+ and arterial diameter by the SNS. Specifically, we test the hypothesis that SNS-evoked TRPV1 channel activation promotes increased global cytosolic Ca2+ and vasoconstriction via multiple pathways including: 1) direct Ca2+ entry through TRPV1 channels and, 2) TRPV1-mediated cation influx, membrane potential (VM) depolarization and enhanced VDCC activity. In Aim 2, we combine in vivo measurements of arterial diameter, ASM Ca2+ and CBF to elucidate the role of TRPV1 channels in promoting the maintenance of CBF during acute decreases in blood pressure that mimic hemorrhagic shock. In summary, this proposal is designed to provide unprecedented resolution of TRPV1 channel impact on arterial diameter and CBF. Identifying a key role for ASM TRPV1 in promoting CBF during acute decreases in blood pressure has the potential to provide a wealth of new information of great benefit to individual shock patients and our society at large.